We aim to understand the molecular pathogenesis of pediatric high-grade gliomas (HGG). This disease represents approximately 20% of pediatric central nervous system tumors and 70-90% of patients survive less than 2 years. These dismal statistics highlight the need to identify appropriate molecular targets for HGG to develop novel therapies for children. Unfortunately, the limited knowledge regarding the genetic characteristics of pediatric HGG has hindered the efforts to design more effective treatments, which are primarily based on findings from adult HGG. In an effort to close this gap of knowledge, our lab has done genome-wide analyses to define genetic alterations (i.e. gains/losses and mutations) in a unique collection of pediatric HGG tumor samples; including specimens from diffuse intrinsic pontine gliomas (DIPG) that are rarely sampled because of their location. As a consequence, little is known of their biology. We found that children display genomic alterations that are distinct from adult cases. The receptor tyrosine kinase, insulin growth factor 1 receptor (IGF1R) was among one of the genes that was frequently altered in a subset of pediatric HGG, including DIPG. Based on these results, we tested the hypothesis that overexpression of IGF1R may act as a driving oncogenic alteration in primary astrocytes. Preliminary data confirmed that overexpression of IGF1R in p53-null primary astrocytes produced high grade gliomas in a rapid and reproducible manner following intracranial implantation. This model system will be used to: i) characterize the mechanism by which IGF1R drives astrocytic tumorigenesis; and ii) evaluate the effects of targeting IGF1R signaling in this glioma mouse model. We will study the signaling mechanism to pin-point the downstream targets of IGF1R activation that regulate astrocytic growth and tumorigenesis. Additionally, gene expression profiling will allow us to determine the similarities and differences between our mouse model and the human disease to assess fidelity of the model and its utility to study treatment responses. Our studies will also include 3 independent human pediatric HGG xenografts with and without IGF1R overexpression to evaluate to role of IGF1R in the context of different pediatric HGG to identify common signaling mechanisms. Lastly, we will block IGF1R signaling in the IGF1R-driven glioma model with the clinically relevant dual kinase inhibitor, OSI-906, to provide insight into therapeutic benefits by targeting this signaling axis. Addressing these aims, will also characterize a novel IGF1R-driven glioma model that can be used as a tool for investigators to study the biology of this disease and for preclinical testing. Overall, the goal of this research is to improve the understanding of HGG in children by studying a gene that is amplified and overexpressed in a subset of these patients. This proposal aims to reveal opportunities to develop and pursue specific molecular therapeutic strategies relevant for the pediatric population. PUBLIC HEALTH RELEVANCE: High-grade glioma (HGG) comprise approximately 20% of all childhood tumors of the central nervous system, with a dismal 2 year survival rate of <10-30%. The molecular signature of this pediatric disease is understudied and development of new therapies have been unsuccessful, possibly due to its reliance on data from adult HGG. There is a need for improved understanding of pediatric HGG to identify relevant therapeutic targets for kids.